Heartburn, or pyrosis, is a sensation of pain or burning located substernally or high in the epigastrium with radiation into the neck and occasionally to the arms, associated with regurgitation of acid-peptic gastric juice into the esophagus. Occasional heartburn is common in normal persons, but frequent and severe heartburn is generally a manifestation of esophageal dysfunction. Heartburn may result from abnormal motor activity or distention of the esophagus reflux of acid or bile into the esophagus, or direct esophageal mucosa irritation (esophagitis).
Heartburn is most often associated with gastroesophageal reflux. In this setting, heartburn typically occurs after a meal, with stooping or bending, or when the patient is supine. It may be accompanied by the spontaneous appearance in the mouth of fluid which may be salty, sour, or bitter and green or yellow. Heartburn may arise following the ingestion of certain foods (e.g. citrus fruit juices) or drugs (e.g. alcohol or aspirin).
Reflux esophagitis consists of esophageal mucosal damage resulting from reflux of gastric or intestinal contents into the esophagus. Esophagitis, an inflammation of the esophagus from regurgitation of acid gastric contents, producing substernal pain, develops when the mucosal defenses that normally counteract the effect of injurious agents on the esophageal mucosa succumb to the onslaught of the refluxed acid pepsin or bile. Mild esophagitis shows microscopic changes of mucosal infiltration with granulocytes or eosinophils, hyperplasia of basal cells, and elongation of dermal pegs. Erosive esophagitis shows endoscopically visible damage to the mucosa in the form of marked redness, friability, bleeding, superficial linear ulcers, and exudates.
Known antagonists of the histamine H.sub.2 receptor include cimetidine, ranitidine, nizatidine, and famotidine. Famotidine (available from Merck & Co., Inc., Whitehouse Station, N.J., under the name PEPCID.RTM.), is 3-{{{2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-4-(aminosulfon yl)propanimidamide, having the structural formula: ##STR1## The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both acid concentration and volume of gastric secretion are reduced by famotidine. Famotidine is used to treat acid-related disorders such as gastric and duodenal ulcer, gastroesophageal reflux disease and Zollinger Ellison syndrome. Its safety and efficacy have been well established in controlled clinical studies. It is used by over 31 million patients worldwide.
Gitlin et al., Amer. Journal of Gastroenterology (1985) vol. 80 pp. 840 examines famotidine efficacy in the treatment of active duodenal ulcers. 20 mg twice daily, 40 mg twice daily and 40 mg at bedtime were administered over a four week period. Healing rates of 67, 75, 70% , respectively, were seen.
Similarly, Miyoshi et al., Naika Hokan (1987) vol. 34 pp. 442-457 demonstrates the efficacy of famotidine as a gastritis therapy. Miyoshi et al. evaluated dosage regimens of 5, 10, or 20 mg twice daily in the treatment of gastritis symptom relief. Patients treated with 10 to 20 mg of famotidine had fewer erosions and mucosal haemorrhages than those treated with 5 mg famotidine.
McCallum et al., Dig. Dis. Sci. (1985) vol. 30 pp. 1139-1144 describes a study of healthy patients demonstrating that 5 mg of famotidine produces has an effect on gastric acid secretion. Laskin et al., J. Clin. Pharmacol. (1993) vol. 33 pp. 636-639 describes a study demonstrating that single doses of 5 and 10 mg of famotidine produces statistically significant decreases in intragastric acidity, beginning at 90-100 minutes and persisting for approximately 9 hours.
Administration of H.sub.2 antagonists before ingestion of a heartburn inducing meal may reduce the amount of gastric acid produced and prevent heartburn symptoms. However, H.sub.2 antagonists do not neutralize gastric acid, and the onset of the antisecretory effect of H.sub.2 antagonists is not instantaneous. Therefore, administration of an H.sub.2 antagonist following a meal will not substantially prevent heartburn and related symptoms. Antacids are known to neutralize acid in the stomach and may also act locally in the distal esophagus. Antacids are not known to prevent heartburn when taken before food or beverages which may provoke symptoms.
Wolfe, U.S. Pat. No. 5,229,137, describes compositions and methods which require the simultaneous administration of an H.sub.2 antagonist with an antacid to provide relief from pain, discomfort and symptoms associated with episodic heartburn EP 138 540 describes oral compositions containing cimetidine and aluminum hydroxide-magnesium carbonate co-dried gel for treating duodenal, gastric, recurrent and stomal ulceration, and reflux esophagitis. EP 233 853 describes effervescent compositions containing cimetidine and sodium bicarbonate for treating duodenal and gastric ulcers. EP 290 229 describes compositions containing cimetidine, aluminum hydroxide gel, and magnesium hydroxide, for treating duodenal, gastric, recurrent and stomal ulceration, and reflux esophagitis. EP 294 933 describes compositions containing cimetidine, aluminum hydroxide gel and magnesium hydroxide, for treating duodenal, gastric, recurrent and stomal ulceration, and reflux esophagitis. The antacid is described as providing rapid relief from the symptoms of excess stomach acidity by neutralizing acid and the cimetidine is described as bringing about more sustained relief by inhibiting secretion of acid. WO 92/00102 describes coadministration of H.sub.2 antagonists with antacids for treating gastric disorders such as hyperacidity. WO 93/12779 describes compositions of H.sub.2 antagonists with antacids for treating gastric disorders such as hyperacidity. EP 600 725 describes compositions of famotidine with antacids for treating gastrointestinal distress.
Applicants have now found that administration to a patient of a composition comprising an H.sub.2 antagonist and antacid, following a heartburn inducing event such as consumption by the patient of heartburn-inducing food or beverage, but prior to development of heartburn, is an effective means for preventing heartburn or reducing the frequency and severity of postprandial heartburn.
Applicants have also found that compositions comprising about 10 mg famotidine and between about 15 and 46 mEq acid neutralizing capacity of antacid are effective for preventing and treating heartburn symptoms.